Neurotrophins, such as NGF and BDNF, are prominent regulators of neuronal survival, growth and differentiation during development of the vertebrate nervous system. They also play an important role in higher order functions, such as pain, addiction, mood disorders and learning and memory. A major problem in the field is to explain how neurotrophins are able to carry out these diverse activities through receptor signaling. The actions of neurotrophins are dictated by two cell surface receptors, Trk tyrosine kinases and the p75 receptor. We are interested in the role of Trk receptor signaling in dictating neuronal responsiveness by neurotrophins. In the next grant period, we will focus upon a multifunctional scaffold protein called ARMS/Kidins220, which is a principal substrate of Trk receptors. This protein is heavily tyrosine phosphorylated by neurotrophins and plays a critical role in the branching of cortical and hippocampal dendrites; in the turnover of cortical spines; and also in modulating basal synaptic transmission. The mechanisms by which ARMS/Kidins220 are involved in neurodegeneration in the entorhinal cortex, as well as receptor tyrosine kinase signaling and interactions with glutamate receptors will be studied. Our investigation is directly relevant to understanding the mechanism of trophic factors and their roles in neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington's and Alzheimer's diseases, as well as psychiatric disorders, such as anxiety and depression.